There is increasing interest in vitamin D nutrition during pregnancy because of widespread reports of a high prevalence of low vitamin D status in pregnant women. While vitamin D is important for calcium and phosphorus homeostasis and for bone health, it also plays important roles in many other physiologic functions in the body. Consistent with the expanded role of vitamin D, recent observational studies have demonstrated that low vitamin D status in pregnancy is associated with multiple potential adverse maternal, fetal, and infant outcomes and contributes to low vitamin D status in infants at birth. Therefore, an overview of the current understanding of vitamin D nutrition in pregnancy and a review of the results of studies to optimize vitamin D status during pregnancy and in the offspring is of public health importance and timely.

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Vitamin D requirement during pregnancy

In order to determine the vitamin D requirement during pregnancy, one needs to define the target serum 25(OH)D concentration considered as "normal" or "optimal". As noted previously, the recent Institute of Medicine report recommends that a circulating serum 25(OH)D concentration of 50 nmol/L is adequate to meet the needs for calcium homeo-stasis and bone health in adults.7 The recommended dietary allowance of 600 IU/day for both pregnant and lactating women in the US and Canada would theoretically meet the daily requirement in 97.5% of the population for achieving the recommended target serum 25(OH)D concentration of 50 nmol/L. However, a committee of vitamin D experts99 and the Endocrine Society8 recommend a target serum concentration >75 nmol/L based on the available evidence in order to achieve optimal benefits for skeletal health as well as potential nonskeletal benefits. A target concentration of 75 nmol/L is consistent with the cord blood 25(OH)D level reported in some studies as being protective against lower respiratory infection, wheezing, and eczema in infants.94-96 To achieve a target serum concentration > 75 nmol/L, the society recommends a daily vitamin D intake of 1500-2000 IU. These recommendations are based mostly on studies from the US and may not be applicable worldwide due to differences in baseline vitamin D status,100 particularly in populations where severe vitamin D deficiency is prevalent.

A review of the few previous randomized controlled trials of vitamin D supplementation during pregnancy indicates that doses of 400-1600 IU/day were insufficient in achieving a mean serum 25(OH)D concentration >=50 nmol/L in most of the studies.41 In a recent vitamin D supplementation trial from the UK, a multiethnic group of 180 pregnant women were randomized at 27 weeks' gestation to receive a single oral dose of 200,000 IU of vitamin D, daily supplementation of 800 IU, or no treatment.33 The median serum 25(OH)D concentration in the 800 IU/day group at study entry was 26 nmol/L (interquartile range 22-37), and the median 25(OH)D concentration at delivery following supplementation was 42 nmol/L (interquartile range 31-76). Only 30% of the women treated with 800 IU/day of vitamin D achieved a serum 25(OH)D concentration >50 nmol/L. In another study from the UK,101 the investigators recruited 80 consecutive pregnant women from minority ethnic backgrounds whose serum 25(OH)D concentrations at the first antenatal visit were <20 nmol/L. These subjects with very low vitamin D status were started on 800 IU/day of vitamin D, increased to 1600 IU/day at 36 weeks' gestation if serum 25(OH)D was still low. The mean serum 25(OH)D concentration increased from 14.4 ± 2.3 nmol/L at enrollment to only 28.5 ± 15.8 nmol/L at delivery despite supplementation of 800-1600 IU/day. These two studies and older research41 indicate that, in populations with a high prevalence of severe vitamin D sufficiency, supplementation up to 1600 IU/day may be inadequate to achieve the recommended target serum 25(OH)D concentration of 50 nmol/L.7 In two recent studies from India, which used large single-dose supplementation of 120,000 IU at the fifth and seventh month of gestation15 or at the second and third trimester,69 only 25% and 62%, respectively, achieved a serum 25(OH)D concentration >50 nmol/L. The recent Cochrane review of vitamin D supplementation alone during pregnancy79 considered five trials that compared the effects of supplementation with placebo or no supplementation.33,73,77,78,102 The review concluded that vitamin D supplementation increases serum 25(OH)D concentrations during pregnancy. Of note, in two of the five studies, the mean concentration of 25(OH)D after supplementation was <50 nmol/L,33,78 and serum 25(OH)D was not measured in one study.73 All these studies underscore the uncertainty about the amount of vitamin D supplementation required to optimize vitamin D status in pregnancy and which would be generalizable worldwide.

As mentioned earlier, the criteria for defining what constitutes "normal" vitamin D status are controversial. The Institute of Medicine7 considers a serum 25(OH)D concentration >50 nmol/L as acceptable, while the Endocrine Society and vitamin D experts recommend >75 nmol/L.8,99 A recent study among traditional populations in Tanzania with type VI (dark) skin color living in a sun-abundant environment recommended a mean serum 25(OH)D concentration of 115 nmol/L in nonpregnant adults and 139 nmol/L in pregnant women.57 The question then is: what serum concentration of 25(OH)D is "normal" in adults, including during pregnancy? While the debate and studies to identify optimal serum 25(OH)D concentration continue, it is prudent to monitor vitamin D status and develop strategies to ensure at least a minimum serum 25(OH)D concentration of 50 nmol/L in pregnant women, especially in an environment where vitamin D deficiency is endemic.

In studies of adults and nonpregnant women, a vitamin D intake of up to 10,000 IU/day is associated with achievement of a serum 25(OH)D concentration >= 80 nmol/L without vitamin D toxicity.103,104 From a review of previous studies, an additional daily intake of 100 IU of vitamin D increases the serum 25(OH)D concentration by 1-2 nmol/L.7,105 Therefore, knowing the population baseline serum 25(OH)D concentration, it is possible to estimate the vitamin D intake required to replete body stores and achieve an expected target serum 25(OH)D concentration. Because of controversy surrounding vitamin D requirements during pregnancy, investigators from South Carolina performed a comprehensive, large, randomized controlled study of vitamin D supplementation in pregnancy to achieve optimal vitamin D status, defined as a serum 25(OH)D concentration >= 80 nmol/L at delivery.18 Based on the pharmacokinetics of vitamin D, the authors investigated the safety and effectiveness of high-dose vitamin D supplementation. They hypothesized that daily vitamin D3 supplementation of 4000 IU/day would be more effective than 2000 IU and a standard dosing regimen of 400 IU in achieving a serum 25(OH)D concentration of >80 nmol/L without any safety issues referable to vitamin D supplementation. In this study, women of varied ethnicity were randomized at <16 weeks' gestation into 4000 IU, 2000 IU, or 400 IU daily treatment groups, which were continued through to delivery. Subjects with an initial baseline 25(OH)D > 100 nmol/L were allocated to vitamin D3 2000 IU/day or 400 IU/day. Vitamin D status was monitored in the mother during pregnancy and in cord blood as a surrogate marker of infant vitamin D status at birth. The safety outcome measures monitored were serum 25(OH)D concentration, hypercalcemia, and hypercalciuria.

Of the 494 women enrolled in the study, 350 continued participation until delivery. The mean serum 25(OH)D concentrations at entry to the study were not significantly different between the groups. However, mean serum 25(OH)D concentrations at delivery were significantly different, with the highest level achieved by the group on 4000 IU/day. The mean serum 25(OH)D concentrations at delivery in the 4000 IU, 2000 IU, and 400 IU daily groups were 110 ± 40.4, 98.3 ± 34.2, and 78.9 ± 36.5 nmol/L respectively, (P = 0.0001). Similarly, 82%, 71%, and 50%, respectively, of the mothers on 4000 IU, 2000 IU, and 400 IU of vitamin D daily achieved a serum 25(OH)D concentration >80 nmol/L (P = 0.0001). The authors also found that supplementation with 4000 IU/day was associated with maximal 1,25(OH)2D production. Although the implications of this finding are unclear, they require exploration in future studies because of the possible role of 1,25(OH)2D in control of multiple gene expression. Neonatal serum 25(OH)D concentrations correlated significantly with maternal serum 25(OH)D at delivery and were significantly different by dosing group. If the Institute of Medicine's target of a serum 25(OH)D concentration >= 50 nmol/L7 was adopted for neonatal vitamin D status, 79%, 58%, and 40%, respectively, of the infants of mothers on 4000, 2000, and 400 IU per day achieved adequate vitamin D status (P = 0.0001). There were no adverse events related to vitamin D supplementation during the study. Based on this protocol, the authors concluded that 4000 IU/day of vitamin D3 supplementation is safe and most effective in achieving vitamin D sufficiency in mothers and adequate vitamin D status in their offspring, irrespective of ethnicity. The authors also found that maternal vitamin D supplementation with 4000 IU/day decreased the risk of combined comorbidities, including infection, preterm birth, gestational diabetes, and pre-eclampsia,82 and suggested that additional studies with adequate power for assessment of other endpoints were needed.

Another recent study from the United Arab Emirates among pregnant Arab women with a high prevalence of vitamin D deficiency also confirmed that 4000 IU/day of vitamin D supplementation was safe and more effective than 2000 IU/day and 400 IU/day in optimizing vitamin D status during pregnancy and in achieving vitamin D sufficiency at birth in mothers and offspring.106 In the United Arab Emirates study, the increment from baseline to delivery was about four-fold higher than expected based on previous pharmacokinetic studies, possibly related to low baseline vitamin D status.100 This indicates that baseline vitamin D status should be taken into consideration when evaluating vitamin D supplementation.100,107

The findings of these recent intervention studies indicate an urgent need for more randomized controlled trials in diverse geographic locations with large sample sizes to identify the vitamin D intake required to optimize vitamin D status, and to assess the effect on pregnancy-related and infant-related complications. Based on biomarkers affected by vitamin D status, and findings from observational studies and recent randomized trials, future studies should include trial arms to achieve serum 25(OH)D concentrations that have been associated with potential extraskeletal benefits8,82,84,94-96 of vitamin D to understand better both the benefits and risks of vitamin D supplementation to mother and offspring.